Arthur B. Schneider

Thyroid Cancer after Exposure to External Radiation: A Pooled Analysis of Seven Studies

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

Thyroid cancer occurring as a late consequence of head and neck irradiation. Evaluation of 1056 patients

From January 1 to September 30, 1974, we examined 1056 of 5266 subjects (20.1%) who had received therapeutic irradiation primarily for infections and inflammatory disease of the upper respiratory tract at our institution during the 1940s and 1950s. The tonsillar and nasopharyngeal region was the treatment site in 85% of those examined. Palpable nodular thyroid disease was found in 16.5%, and nonpalpable lesions were detected by 99m Tc pertechnetate thyroid imaging in an additional 10.7%, for a prevalence of nodular disease of 27.2%. Operation on 71% with nodular disease revealed thyroid cancer in 33% (60 of 182). Preliminary analysis for potential risk factors suggests a correlation between radiation exposure and the presence of thyroid nodules (P less than 0.001). These findings indicate that nodular thyroid disease, both benign and malignant, continues as a major health problem for at least 35 years in exposed subjects.

Exposing the Thyroid to Radiation: A Review of Its Current Extent, Risks, and Implications

Radiation exposure of the thyroid at a young age is a recognized risk factor for the development of differentiated thyroid cancer lasting for four decades and probably for a lifetime after exposure. Medical radiation exposure, however, occurs frequently, including among the pediatric population, which is especially sensitive to the effects of radiation. In the past, the treatment of benign medical conditions with external radiation represented the most significant thyroid radiation exposures. Today, diagnostic medical radiation represents the largest source of man-made radiation exposure. Radiation exposure related to the use of computerized tomography is rising exponentially, particularly in the pediatric population. There is direct epidemiological evidence of a small but significant increased risk of cancer at radiation doses equivalent to computerized tomography doses used today. Paralleling the increasing use of medical radiation is an increase in the incidence of papillary thyroid cancer. At present, it is unclear how much of this increase is related to increased detection of subclinical disease from the increased utilization of ultrasonography and fine-needle aspiration, how much is due to a true increase in thyroid cancer, and how much, if any, can be ascribed to medical radiation exposure. Fortunately, the amount of radiation exposure from medical sources can be reduced. In this article we review the sources of thyroid radiation exposure, radiation risks to the thyroid gland, strategies for reducing radiation exposure to the thyroid, and ways that endocrinologists can participate in this effort. Finally, we provide some suggestions for future research directions.

Radiation-induced tumors of the head and neck following childhood irradiation. Prospective studies

Nodules were found in 1108 subjects who received childhood radiation for benign conditions of the cervical area at our institution. This is 37.5% of 2958 subjects, out of a total of 5379, for whom there is follow-up information. Of the 848 subjects who have had thyroidectomies, 297 (35.0%) had thyroid cancer. In addition to thyroid tumors, salivary, neural, and probably parathyroid tumors also occurred as a late consequence of childhood radiation. Prospective studies of the subjects indicate that thyroid nodules are continuing to occur at a constant rate. The measurement of serum thyroglobulin is helpful in identifying individuals for whom the risk of developing a nodule is increased. Follow-up of patients with nonsurgically-treated nodules indicates that some of their nodules are progressive. At the present time there is no indication that radiation-induced cancers behave differently than ones in other settings. However, some of their characteristics, especially their multicentricity and occurrence in younger individuals, indicate that continued follow-up is necessary. On the basis of the data generated by the follow-up program at our institution and programs elsewhere, recommendations for screening, treatment, and follow-up are made. The recommendations stress the importance of estimating risk based on radiation dose, previous tumors, and serum thyroglobulin, in arriving at clinical decisions for these subjects.

Salivary Gland Neoplasms as a Late Consequence of Head and Neck Irradiation

An increased occurrence of salivary tumors was observed in 1922 patients who received radiation to the tonsils and nasopharynx. Twenty-seven tumors, 19 benign and eight malignant, were found in this group as compared with an expected 0.2 malignant and less than 1 benign tumor. The latent period between the initial radiation treatment and diagnosis ranged from 7 to 32 years. After the first 15 years the incidence (77 cases/10(5) subjects/year) has remained constant and shows no indication of declining. Continued observation for salivary gland tumors is therefore indicated for subjects who received childhood irradiation.

Incidence, prevalence and characteristics of radiation-induced thyroid tumors

Abstract A population of 5,266 persons were known to be at risk for the development of thyroid neoplasms as a result of prior head and neck irradiation for benign conditions received at our institution. We contacted 2,578 (49.0 per cent) of these persons of whom we examined 1,476 (28.0 per cent) and received follow-up data on 713 (13.5 per cent). Prior to the onset of our recall program, 209 persons had had thyroid surgery (9.4 per cent of those with adequate follow-up data). The incidence of thyroid operations after the initial radiation treatment was low for 10 years and then increased continuously for at least 25 years. The incidence of carcinoma found at operations performed before the recall program and after was similar (37.1 per cent before versus 36.2 per cent after). This high percentage, which was not changed by the follow-up and examination program, supports the conclusion that the probability of finding thyroid cancer in a nodular gland is increased in irradiated patients. No risk factors were found in irradiated subjects that distinguished between malignant and benign disease. Of 50 patients who were examined and who had a history of prior thyroid surgery, 18 (36 per cent) had evidence of new thyroid tumors. In this limited group, thyroid suppressive therapy appeared to prevent recurrences. However, a larger trial to assess the value of thyroid suppression is still warranted. One subject is known to have died of thyroid cancer.

Plasma Thyroglobulin in Detecting Thyroid Carcinoma after Childhood Head and Neck Irradiation

The level of thyroglobulin in plasma was measured in 904 subjects with a history of head and neck irradiation during childhood to evaluate its potential value in screening for and differentiating thyroid neoplasms. Mean plasma thyroglobulin level was significantly elevated in subjects with nodular thyroid disease versus those without evidence of nodules (49.8 versus 27.0 ng/ml). However, the overlap with normal subjects does not allow thyroglobulin assays to serve as the only screening procedure. The mean levels in subjects with benign and malignant thyroid nodules were indistinguishable (48.8 versus 53.9 ng/ml). Thirteen percent of otherwise normal-appearing subjects had elevated values that may represent clinically inapparent thyroid disease. It is concluded that in screening large numbers of persons at risk for thyroid neoplasia, thyroglobulin assays are useful in combination with other modes of evaluation. The assay is without value in distinguishing benign from malignant disease.

Recurrence of Thyroid Nodules after Surgical Removal in Patients Irradiated in Childhood for Benign Conditions

To determine the incidence of benign thyroid nodules and the risk factors for their recurrence after surgical removal, we followed 511 patients for 1 to 40.6 years (median, 11.2) after surgery for benign thyroid nodules arising after local irradiation for unrelated benign diseases in childhood. Recurrent thyroid nodules developed in 100 patients (19.5 percent). The risk of recurrence correlated inversely with the amount of thyroid tissue removed. Women had a higher recurrence rate than men (28.4 percent vs. 10.3 percent; P less than 0.05). Among the 299 patients who had been treated with thyroid hormone at the discretion of their physicians to suppress thyroid-stimulating hormone, 25 had recurrences (8.4 percent), as compared with 72 of 201 patients who did not receive thyroid hormone (35.8 percent) (hazard ratio taking into account the extent of surgery and the patients sex, 2.5; 95 percent confidence interval, 1.5 to 4.1). Histologic analysis of the 73 tissue samples from patients with recurrences showed that 14 samples (19.2 percent) were malignant. Thyroid hormone treatment had no effect on the rate of thyroid cancer. We conclude that radiation-associated benign thyroid nodules have a high recurrence rate, similar to that reported among nonirradiated patients with benign thyroid nodules. We also conclude that treatment with thyroid hormone decreases the risk of benign recurrences, particularly in women, but not the risk of cancer.

Radiation-induced thyroid carcinoma. Clinical course and results of therapy in 296 patients.

Of 5379 patients who had received radiation treatment at our institution for benign conditions of the head and neck, 318 developed thyroid cancer 3 to 42 years later. We report follow-up observations (median interval from diagnosis to recurrence or last contact, 10 years; longest interval, 31) for 296 of these patients. Three patients died of thyroid cancer and 40 had recurrences. The rate of recurrence during the 10 years after the detection of thyroid cancer, determined by life-table analysis, was 1.1%/yr. Factors that correlated with the risk of recurrence were tumor size, histologic type, number of lobes involved, vessel invasion, and lymph node metastases. The time from radiation exposure to the discovery of thyroid cancer (latency) and the age at diagnosis both inversely correlated with recurrence. The administration of thyroid hormones reduced the number of recurrences in patients with combined papillary and follicular cancer, but no reductions could be associated with the extent of surgery done or the prophylactic use of radioactive iodine ablation. We conclude that the course of radiation-induced thyroid cancer is the same as that of thyroid cancer found in other settings. We advocate a conservative approach to the treatment of small tumors that have no associated risk for thyroid cancer other than that they developed many years after the patient had been exposed to radiation.

Long-term risks for thyroid cancer and other neoplasms after exposure to radiation.

Radiation-related thyroid cancer continues to be a clinical concern for two reasons: the risks associated with the widespread use of radiation treatments for benign conditions in the middle of the last century persist for decades after exposure; and radiation continues to be an effective component of the treatment of several childhood malignancies. Patients who were irradiated in the head and neck area need to be evaluated for thyroid cancer, benign thyroid nodules, hyperparathyroidism, salivary-gland neoplasms and neural tumors, including acoustic neuromas. Radiation-related thyroid cancers appear to have the same clinical behavior as other thyroid cancers, but many irradiated patients are entering the age range when more aggressive neoplasms occur. In this paper, we review how to approach the clinical management of a patient with a history of radiation exposure in the thyroid area, and how to treat radiation-exposed patients who develop related neoplasms, especially thyroid cancer.